It is known that tumor cells grow fast if they are supplied with nutrients by angiogenesis. However, tumor cells growth during angiogenesis will result in vascular hypoplasia, which in turn results in a lot of leakages in micrometer order on blood vessels. Such a loose structure of blood vessels allows drug penetrate into tumor cells cavity easily. Moreover, since tumor tissue lacks of normal lymphatic network, if drugs enter into tumor cells, it is very difficult to leave through normal lymphoid tissue so that it could prolong residence time of drugs in tumor cells, which is so-called Enhanced Permeability and Retention (EPR) effect. Due to such a property, drugs in a size of from 100 nm˜200 nm is considered be a potential for treating tumor.
Liposomes were first discovered by Alec Bangham, a British scientist, in 1960s. Liposomes are a spherical vesicle composed of a lamellar phase lipid bilayer, which structure is similar to the composition of cell membrane. Liposomes are biocompatible and biodegradable in human body. Liposomes comprise phospholipid, which phosphate end is hydrophilic and lipid end is hydrophobic so that liposomes can be used as a carrier both for hydrophobic and hydrophilic drug. Particle size of liposomes is from tens nanometers (nm) to tens micrometers (μm), they do not easily enter into the blood vessels in normal tissue, since the gaps between normal vascular endothelial cells are closed. However, since the gaps between tumor endothelial cells are enough large to yield the EPR effect, liposomes easily enter tumor endothelial cells and accumulate on tumor sites, thus improve the therapy efficiency of the drug carried on them. Thus, if therapeutic radionuclides are encapsulated in liposomes, it could improve tumor therapeutic effects of β-ray emitted by radionuclides. Methods for labeling radioisotopes onto liposomes are generally divided into two ways. One is a surface labeling method, which comprises directly labeling radionuclides on liposome on which surface bonded with chelators. Another is an embedding (after loading) method, which is the most common method. For example, Bao et al. published that N,N-bis(2-mercaptoethyl)-N′,N′-diethylethylenediamine (BMEDA) labeled with rhenium-188 (Re-188), rhenium-186 (Re-186) and technetium-99m were embedded in liposome and studied its effect on radiotherapy and imaging agents of radiodiagnosis on normal mice (Bao et al. J. Pharm. Sci (2003) 92, 1893-1904; J. Nucl. Med (2003), 44, 1992-1999; U.S. Pat. No. 7,718,160 B2). The common features in the after loading methods for preparing radiolabeled liposomes are: (i) Radioisotopes require the helps of chelators or ionophores to enter into liposomes. Therefore, a step of labeling of chelators with radioisotopes is necessary in this process. (ii) After entering into liposomes, radioisotopes need to react with other chelators or buffers solution to remain within liposomes stably. But there are disadvantages in using the after loading methods for preparing radiolabeled liposomes: (i) The used chelator, i.e. BMEDA is liquid state, it is easy oxidized so that the efficiency labeling with Re-186 or Tc-99m will be reduced. (ii) Additional purifying steps are required because of the low loading efficiency (generally the loading efficiency is about 60% to about 80%). (iii) The kit is un-stable for long time storage so that it should be prepared just before use. Furthermore, the whole labeling process is complex and time-consuming, it will reduce the radioactivity of radiopharmaceuticals to be prepared (for example, Re-188 radionuclides, which half-life is about 16.9 hours) so that the kinds of radioisotopes which can be used are limited.
There are many researches about therapy efficiency of Re-188 or Re-186-radiolabeled liposomes for treating colon cancer, head and neck cancer and breast cancer. In 2010, French et al. studied interventional therapy effect of head and neck cancer with 186Re-liposome (185 MBq (5 mCi)/cm3 tumor) (J Vasc Intery Radiol. 2010; 21(8): 1271-1279) and reported that average tumor volume of the 186Re-Liposome group on post-treatment day-14 was decreased to 87.7±20.1% (<0.001) and radiation absorbed dose on tumor was 526.3±93.3 Gy, which is far higher than 186Re-perrhenate and 186Re-BMEDA groups. And no systemic toxicity was observed. In 2012, Phillips et al. used 186Re-Liposome for treatment of glioblastoma at a dose of up to 1850 Gy by local injection and no overt clinical or microscopic evidence of toxicity was found (Neuro-Oncology 2012; 14(4):416-425). Animals treated with 186Re-Liposomes in a dose of 1850Gy had a median survival of 126 days (95% confidence interval [CI], 78.4-173 days), while control group is 49 days (95% CI, 44-53 days). And no systemic toxicity was observed. Although it showed that 186Re-Liposome is effective to treat the head and neck cancer and glioblastoma, the administration is limited to local injection, which will limit 186Re-Liposome to only use in the treatment of carcinoma in situ, and cannot be used in treatment of metastatic cancer.
Comparing with rhenium-186, rhenium-188 is a carry free and can be obtained in high radioactivity from tungsten-188 generator, thus it is more convenient for clinical use. Further, the half-life of rhenium-188 is 16.9 hr which is shorter than rhenium-186 (its half-life is 90 hr), thus rhenium-188 is safer and can use lower dose in clinical use.